Biologically, cholesterol is eliminated from the body by conversion into bile acids and excretion as neutral steroids. Bile acids are synthesized from cholesterol in the liver and enter the bile as glycine and taurine conjugates. They are released in salt form in bile during digestion and act as detergents to solubilize and consequently aid in the digestion of dietary fats. Following digestion, bile acid salts are mostly reabsorbed by active transport in the ileum, complexed with proteins, and returned to the liver through hepatic portal veins. The small amount of bile acid salts not reabsorbed in the ileum is excreted via the distal ileum and large intestine, as a portion of the fecal material.
Therefore, reabsorption of bile acids, which can be present as the corresponding salts or conjugates, from the intestine conserves lipoprotein cholesterol in the bloodstream. As such, reducing reabsorption of bile acids within the intestinal tract can lower levels of bile acids circulating in the enterohepatic system thereby promoting replacement of bile acids through de novo synthesis from cholesterol, in the liver. The result is a lowering of circulating blood cholesterol levels.
One method of reducing the quantity of bile acids that are reabsorbed is the oral administration of compounds that sequester the bile acids within the intestinal tract and cannot themselves be absorbed. The sequestered bile acids consequently are excreted.
A need exists for sequestrants that bind bile acid salts and conjugates.